3H-Pyrazolo[4,3-f]quinoline-Based Kinase Inhibitors Inhibit the Proliferation of Acute Myeloid Leukemia Cells In Vivo

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F21%3A00545107" target="_blank" >RIV/61388963:_____/21:00545107 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68378050:_____/21:00556295 RIV/61989592:15310/21:73610086

Výsledek na webu

<a href="https://doi.org/10.1021/acs.jmedchem.1c00330" target="_blank" >https://doi.org/10.1021/acs.jmedchem.1c00330</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.1c00330" target="_blank" >10.1021/acs.jmedchem.1c00330</a>

Jazyk výsledku

angličtina

Název v původním jazyce

3H-Pyrazolo[4,3-f]quinoline-Based Kinase Inhibitors Inhibit the Proliferation of Acute Myeloid Leukemia Cells In Vivo

Popis výsledku v původním jazyce

The 3H-pyrazolo[4,3-f]quinoline moiety has been recently shown to be a privileged kinase inhibitor core with potent activities against acute myeloid leukemia (AML) cell lines in vitro. Herein, various 3H-pyrazolo[4,3-f]quinoline-containing compounds were rapidly assembled via the Doebner–Povarov multicomponent reaction from the readily available 5-aminoindazole, ketones, and heteroaromatic aldehydes in good yields. The most active compounds potently inhibit the recombinant FLT3 kinase and its mutant forms with nanomolar IC50 values. Docking studies with the FLT3 kinase showed a type I binding mode, where the 3H-pyrazolo group interacts with Cys694 in the hinge region. The compounds blocked the proliferation of AML cell lines harboring oncogenic FLT3-ITD mutations with remarkable IC50 values, which were comparable to the approved FLT3 inhibitor quizartinib. The compounds also inhibited the growth of leukemia in a mouse-disseminated AML model, and hence, the novel 3H-pyrazolo[4,3-f]quinoline-containing kinase inhibitors are potential lead compounds to develop into anticancer agents, especially for kinase-driven cancers.

Název v anglickém jazyce

3H-Pyrazolo[4,3-f]quinoline-Based Kinase Inhibitors Inhibit the Proliferation of Acute Myeloid Leukemia Cells In Vivo

Popis výsledku anglicky

The 3H-pyrazolo[4,3-f]quinoline moiety has been recently shown to be a privileged kinase inhibitor core with potent activities against acute myeloid leukemia (AML) cell lines in vitro. Herein, various 3H-pyrazolo[4,3-f]quinoline-containing compounds were rapidly assembled via the Doebner–Povarov multicomponent reaction from the readily available 5-aminoindazole, ketones, and heteroaromatic aldehydes in good yields. The most active compounds potently inhibit the recombinant FLT3 kinase and its mutant forms with nanomolar IC50 values. Docking studies with the FLT3 kinase showed a type I binding mode, where the 3H-pyrazolo group interacts with Cys694 in the hinge region. The compounds blocked the proliferation of AML cell lines harboring oncogenic FLT3-ITD mutations with remarkable IC50 values, which were comparable to the approved FLT3 inhibitor quizartinib. The compounds also inhibited the growth of leukemia in a mouse-disseminated AML model, and hence, the novel 3H-pyrazolo[4,3-f]quinoline-containing kinase inhibitors are potential lead compounds to develop into anticancer agents, especially for kinase-driven cancers.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

1520-4804

Svazek periodika

64

Číslo periodika v rámci svazku

15

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

16

Strana od-do

10981-10996

Kód UT WoS článku

000685644300027

EID výsledku v databázi Scopus

2-s2.0-85112395988